TY - JOUR
T1 - Contiguous gene deletion of ELOVL7, ERCC8 and NDUFAF2 in a patient with a fatal multisystem disorder
AU - Janssen, Rolf J R J
AU - Distelmaier, Felix
AU - Smeets, Roel
AU - Wijnhoven, Tessa
AU - Østergaard, Elsebet
AU - Jaspers, Nicolaas G J
AU - Raams, Anja
AU - Kemp, Stephan
AU - Rodenburg, Richard J T
AU - Willems, Peter H M G
AU - van den Heuvel, Lambert P W J
AU - Smeitink, Jan A M
AU - Nijtmans, Leo G J
N1 - Keywords: Abnormalities, Multiple; Acetyltransferases; DNA Repair Enzymes; Fatal Outcome; Fatty Acids; Female; Gene Deletion; Humans; Infant, Newborn; Mitochondria; Mitochondrial Proteins; Molecular Chaperones; Mutation; Oxidation-Reduction; Phosphorylation; Protein Binding; Transcription Factors
PY - 2009
Y1 - 2009
N2 - Contiguous gene syndromes affecting the mitochondrial oxidative phosphorylation system have been rarely reported. Here, we describe a patient with apparent mitochondrial encephalomyopathy accompanied by several unusual features, including dysmorphism and hepatopathy, caused by a homozygous triple gene deletion on chromosome 5. The deletion encompassed the NDUFAF2, ERCC8 and ELOVL7 genes, encoding complex I assembly factor 2 (also known as human B17.2L), a protein of the transcription-coupled nucleotide excision repair (TC-NER) machinery, and a putative elongase of very long-chain fatty acid synthesis, respectively. Detailed evaluation of cultured skin fibroblasts revealed disturbed complex I assembly, depolarization of the mitochondrial membrane, elevated cellular NAD(P)H level, increased superoxide production and defective TC-NER. ELOVL7 mRNA was not detectable in these cells and no alterations in fatty acid synthesis were found. By means of baculoviral complementation we were able to restore the aberrations, thereby establishing causative links between genotype and cell-physiological phenotype. This first chromosomal microdeletion illustrates that beside primary defects in mitochondrial genes also additional genes possibly contribute to the disease phenotype, providing an additional explanation for the broad clinical symptoms associated with these disorders.
AB - Contiguous gene syndromes affecting the mitochondrial oxidative phosphorylation system have been rarely reported. Here, we describe a patient with apparent mitochondrial encephalomyopathy accompanied by several unusual features, including dysmorphism and hepatopathy, caused by a homozygous triple gene deletion on chromosome 5. The deletion encompassed the NDUFAF2, ERCC8 and ELOVL7 genes, encoding complex I assembly factor 2 (also known as human B17.2L), a protein of the transcription-coupled nucleotide excision repair (TC-NER) machinery, and a putative elongase of very long-chain fatty acid synthesis, respectively. Detailed evaluation of cultured skin fibroblasts revealed disturbed complex I assembly, depolarization of the mitochondrial membrane, elevated cellular NAD(P)H level, increased superoxide production and defective TC-NER. ELOVL7 mRNA was not detectable in these cells and no alterations in fatty acid synthesis were found. By means of baculoviral complementation we were able to restore the aberrations, thereby establishing causative links between genotype and cell-physiological phenotype. This first chromosomal microdeletion illustrates that beside primary defects in mitochondrial genes also additional genes possibly contribute to the disease phenotype, providing an additional explanation for the broad clinical symptoms associated with these disorders.
U2 - 10.1093/hmg/ddp276
DO - 10.1093/hmg/ddp276
M3 - Journal article
C2 - 19525295
SN - 0964-6906
VL - 18
SP - 3365
EP - 3374
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 18
ER -
